LAUSR

Abstract Protein-based therapeutics are significantly reaching the market owing to strides in genetic engineering and target specific drug design. However, majority of the products are available as parenteral and subcutaneous dosage forms. The lungs provide a noninvasive passage for systemic absorption of proteins, with advantages like large surface area (50–75 m2), milder local microenvironment and proteolytic activity as compared to the gastrointestinal tract and a permeable epithelial layer with perfuse vasculature. Even so, the proteins delivered to the lungs are subjected to some degradation via proteolytic enzymes, macrophage assisted clearance, degradation due to chemical destabilization and physical hindrances to permeation. Recent research has been targeted towards identifying these challenges and using formulation development as a tool to overcome one or several of these questions. Preparation of nano-sized and micron-sized polymeric or lipid-based protein formulations offers unmatched advantages such as sustained protein release, distribution and retention in lungs and stabilizing by shielding from local microenvironment. However, degradation of proteins while manufacturing, regulation of particle size, scale-up, long-term safety for chronic conditions (like diabetes or growth hormone deficiency) and translation from bench-to-bedside are some major challenges. Strategies for pulmonary permeation enhancement via paracellular and trans-cellular mechanisms and protein stabilization by prevention of degradation have also been evaluated. This review provides in-depth summary to identify and evaluate the potential of the pulmonary route for delivery of therapeutic proteins.